A Novel Agent for Relapsed/Refractory Myeloma

Improved responses and survival have been realized in myeloma via combinations of immunomodulatory agents, proteasome inhibitors, and plasma-cell–targeting monoclonal antibodies. However, patients who develop treatment resistance have had limited therapeutic options. Investigators now report the results of a multicenter, industry-sponsored, open-label phase 1–2 trial of the novel oral cereblon modulator mezigdomide in combination with dexamethasone in patients with relapsed and refractory multiple myeloma.

The dose- and schedule-finding phase 1 cohort comprised 77 patients and the dose-expansion phase 2 cohort comprised 101 patients. Eligible patients had received three or more prior lines of therapy, including lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody, and had disease progression within 60 days of the most recent antimyeloma therapy.

The recommended phase 2 mezigdomide dose was 1.0 mg once daily in combination with dexamethasone on 28-day cycles of 21 days on treatment followed by 7 days off. At a median follow-up of 7.5 months, the overall response rate in the phase 2 cohort was 41%, including partial response in 16% and very good partial response in 20%. The median progression-free survival (PFS) was 4.4 months. Grade 3–4 toxicities included neutropenia in 76% of patients and infection in 35%; mezigdomide dose reductions occurred in 29% and treatment was discontinued in 6%. There were eight deaths: five from infection, two from myeloma progression, and one from unknown cause.